MXPA97003869A - Benzamida enterocinet - Google Patents

Abstract

The present invention relates to a novel benzamide derivative of formula (I). Pharmaceutical compositions comprising said novel compound methods for the preparation of compounds and compositions, and the use thereof as a medicament, are described in particular for the treatment of conditions involving decreased bowel motility.

Description

BENZflMIDA ENTEROCINETICP DESCRIPTIVE MEMORY The present invention relates to a novel benzarnide derivative and the pharmaceutically acceptable acid addition salts thereof, pharmaceutical compositions comprising said novel compound, methods for preparing said compounds and compositions, and the use of the same as medicament, in particular in the treatment of conditions involving impaired bowel motility, especially of the colon. In EP-0,389,037-A, published on September 26, 1990, it is described that N- (3-hydroxy-4-piper.idinyl) (dihydrobenzofuran or dhydro-2H-benzopyran) carboxamide derivatives have stimulant properties. Gastrointestinal motility. In EP-0445, 862-ft, published on September 11, 1991, it is described that N- (4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyrancarboxamide derivatives also have gastrointestinal motility stimulating properties. The compound of interest of the present application differs from them by exhibiting superior enterokinetic properties The present invention relates to a compound of formula and pharmaceutically acceptable acid addition salts thereof. The chemical name of the compound of formula (I) is 4-arni.no-5-chloro-2,3-di-idro-N-Cl- (3-methoxypropyl) -piperidinyl] -7- enzofuranenebox. The pharmaceutically acceptable acid addition salts as mentioned above means that they comprise the non-toxic therapeutically active acid addition salts forms, which the compounds of formula (I) are capable of forming. The latter can conveniently be obtained by treating the base form with said appropriate acid. Appropriate acids comprise, for example, inorganic acids such co or hydrohalic acids, for example, hydrochloric or brornhydric acid; sulfuric; nitric; phosphoric and similar acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie, butanedioic acid), maleic, fumaric, alic, tartaric, citric, methanesulphonic, ethanesulfonic, benzenesulonic , p-toluenesulfonic, cyclarnico, salicilico, p-aminosal? c.í l co, pamo co-acids and similar. The term "addition salt", as used above, also includes the solvates which the compounds of formula (I) as well as the salts thereof are capable of forming. Said solvates are, for example, hydrates, alcoholates and the like. Alternatively, the salt form can be converted by treatment with lcali in the free base form, downstream, the term "compound of formula (T)" means the compound of formula (I), as well as the pharmaceutically acceptable acid addition salts of the ism, unless otherwise mentioned. Interesting compounds of formula (I) are acid addition salts which are formed by treatment of the base form of the compound of formula (I) with hydrohalic acids or butanedioic acid. Preferred compounds of formula (I) are 4-amino-5-chloro-2,3-d-aro-N- [I- (3-meo-oxo-propyl) -4-p-peronium hydrochloride. ? n? l] -7-benzofurancarboxar? u da and butanedioate of 4-am? no-5-chloro-2,3-d? h? dro-N-C l- (3-rnetoxipropil) -4-p? peridin I] -7-benzofurancarboxamide (1: 1). The compounds of formula (I) can be prepared according to methods which are described in EP-0 389, 037-A and EP-0,445,862-A. Several preparation alternatives are shown below. In the following preparations, the reaction products can be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, distillation, crystallization, trituration and chromatography. . The compounds of formula (I) can be prepared by N-alkylation of an intermediate of formula (II) with alkylating reagent of formula (ITT), wherein U is an appropriate residual group such as halogen, for example, chloro; or a residual sulfonyloxy group, for example, methanesulfon loxi (rnesylate) or a p-toluenesulfon-lox? (tosyla + o) in a solvent inert to the reaction such as a suitable dipolar solvent, for example, dirnethyl ormamide, in the presence of an appropriate base such as, for example, tpeti lamina. An appropriate catalyst such potassium iodide can also be added to increase the speed of the reaction. (m) (p) The compound of formula (I) can also be prepared by an N-acylation reaction of a carboxylic acid of formula (IV) or a reactive termediary thereof and an amine of formula (V). Said N-acylation reaction can be carried out by stirring the two reagents in a reaction-inert solvent, such as a chlorinated hydrocarbon, for example chloroform, or an aromatic hydrocarbon, for example toluene.

CH3-0- (CH2) 3 --N) - NH2 - CD 00 (TV) The aforementioned intermediates are known in the art or the preparation thereof is mentioned in EP-0,389, 037-A and EP-0, 445, 862-fi. The compounds of formula (I) possess excellent stimulation properties of intestinal motility. In particular, the present compounds of formula (I) show important motility-enhancing effects on the large intestine and the small intestine. In other words, the present compounds of formula (I) have enterokinetic properties. These properties are supported by the pharmacological examples described below. The present compounds of formula (I) improve the non-cholinergic non-adrenergic excitation (NANO and the propulsion of feces through the large intestine), they also accelerate the gastric emptying and the contractile activity of the small intestine, and have a facilitating effect on the Cholinergic nerves These compounds are also lacking antagonistic properties of the 5-H 2 0 5-HT 3 receptor Furthermore, the present compounds also show active m activity, as evidenced by the test "Telemetric recording of colóme mo il ity m conscious dogs. "In view of their useful enteroclar improving properties, the compounds of interest can be formulated in various forms for administration purposes.To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound *, in the form of acidic salt or Basic addition, as the active ingredient, is combined in intimate admixture with a pharmaceutically ac eptable, whose vehicle can take a wide variety of forms, depending on the form of preparation desired for admi stration. These pharmaceutical compositions are desirably in the form of an appropriate unit dose, preferably for oral or rectal administration or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier generally comprises sterile water, at least in large part, although other ingredients, for example, to improve solubility, may be included. Injectable solutions may be prepared, for example, in which the vehicle comprises saline, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancer and / or an appropriate fluoridating agent, optionally combined with appropriate additives of any nature in minor proportions, whose additives do not cause a significant deleterious effect to the skin. Said additives may facilitate administration to the skin and / or may be useful for the preparation of the desired compositions. These compositions can be administered in various ways, for example, as a transdermal patch, as a spot application, or as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dose form as used in the specification and claims refers to physically defined units appropriate as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, tablespoons, teaspoons and the like, and segregated multiples thereof. In view of their ability to stimulate the motility of the intestinal system and in particular their ability to improve the motility of the colon, the compounds of interest are useful for normalizing or improving bowel conduction in subjects suffering from symptoms related to deranged motility. , for example, a decreased pepstalsis of the small and large intestine alone or in combination with delayed gastric emptying. In view of the usefulness of the compounds of the present invention, there is provided a method of treating warm-blooded animals, including humans, that suffer from otility disorders of the intestinal system, such as, for example, constipation, pseudo-obstruction, intestinal atony, intestinal atony post-operatopa, irritable bowel syndrome (IBS), and delayed conduction induced by drugs. In particular, a method of treating disorders of the large bowel motility is provided. The isolate compounds can also be used to facilitate the cleaning of the large intestine or to facilitate intubation and / or endoscopy. Said method comprises the synaptic administration of an effective amount of intestine stimulation (thick and thin) of a compound of formula (I), to warm-blooded animals, including humans. Therefore, the use of a compound of formula (I) co or medicament is provided, and in particular the use of a compound of formula (I) for the manufacture of a medicament for the treatment of conditions involving motility or driving disordered of the large and small intestine. It is contemplated in general. that a therapeutically effective amount would be from about 0.001 mg / kg to almost 10 mg / kg of body weight, preferably from almost 0.02 mg / kg to almost 5 mg / kg of body weight. A method of treatment may also include the administration of the active ingredient over a regimen of between 2 or 4 intakes per day.

EXPERIMENTAL PART EXAMPLE 1 In trichloroethane (1.35 ml), 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in patent EP-0,389,037-A) was suspended and cooled to ± 5 ° C. N, N-diethylethanarnine (0.05 mol) was added dropwise at a temperature lower than 10 ° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 minutes while maintaining the temperature lower than in ° C. The resulting mixture was added dropwise over a period of 20 minutes to a soludon of 1- (3-methox? Propyl) -4-??? er? D? Nam? na (0.05 rnol) in ometane tpclo (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 minutes. Said mixture was washed with water (50 ml). The precipitate was filtered on a glass filter and washed with water and CHCt3. The filtrate was separated in its layers. The separated organic layer was washed with water (50 ml) + 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCT / 2-propanol (7.2 rnl, 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered, washed with 2-propanol (15 ml) and dried (vacuum, 50 ° C), yielding 12.6 g (62%) of 4-arn monohydrochloride? no-5-chloro-2,3-d? h? dro-Np - (3-methox? prop? l) -4-p? pepd? n? 1] -7-benzofurancarboxami a (compound 1).

EXAMPLE 2 A mixture of 4-arn? No-5-chloro-2,3-d? H? Dro-N- (4-p? Pepd? N? L) -7-benzofurancarboxa? N? Da (0.01 mol), 1 -chloro-3-methoxypropane (0.012 mol), N, Nd? et? ietanarn? Na (2.1rnl) and KI (catalytic amount) in N, N-d? met lforrnarnide (75ml) was stirred overnight at 50 ° C. The reaction mixture was cooled. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3 / (CH3? H / NH3_) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in? -ropanol and converted to the hydrochloric acid salt (1: 1) with HCI / 2-propanol. The precipitate was filtered and dried (vacuum, 8Q ° C), yielding 1.40g (35%) of 4-arn? no-5-chloro-2,3-d? h monohydrochloride? dro-N-p- (3-methoxypyrol) -4-p? pepdinil] - 7-benzofurancarboxarnide (compound 1) EXAMPLE 3 Reaction under N2 flow - Acid 4-Ammo-5-chloro-2,3-d? H? Dro-7-benzofurancarboxy 1 (0.18 mol) was dissolved in tetrahydrofuran (360 ml) and this solution was stirred and cooled to ± 3 ° C 1.1 '-Carbonilbi s-lH-irnidazole (0.18 mol) was added in one portion and cooling was interrupted. The mixture was agitated for 75 minutes (it became homogeneous after 30 minutes). A solution of 1- (3-methox? Pro? 1) -4-piperidine ma (0.18 mol) in tetrahydrofuran (90 ml) was added dropwise (increase in exothermic temperature from 23 ° C to 27 ° C) . The reaction mixture was stirred for 24 hours. More l, Carbon-lb? S-lH-? M? Dazole (0.0125 mol) was added and the reaction mixture was stirred for 75 minutes. More l- (3-rnetox? Prop? L) -4 - ?? per? D? Narnma (0.0125 mol) was added (in 10 ml of THF). The resulting reaction mixture was stirred for 3 hours at room temperature, then for 2.5 hours at reflux temperature. Then, the mixture was stirred for 13 hours, allowing it to cool to room temperature. The solvent was evaporated. The residue was stirred for 8 hours in water (360 ml) and the precipitate was filtered, washed with water, then dried (vacuum, 30 ° C), yielding 62.9 g (95%) of 4-ammonohydrate monohydrate. -chloro-2,3-d? h? dro-Np- (3 ~ meto? prop? l) -4 - ?? per? d? n? 1] -7-benzofurancarboxamide; p. of f. of 9, 7 ° C (compound 2).

EXAMPLE 4 Compound (2) (5 g, 0.0129 mol) was dissolved in hot ethanol (25 ml). A solution of (+) ~ (S) ~ lactic acid (1.45 g, 0.0135 mol) in ethanol (10 rnl) was added. Under continuous stirring, the crystallization started at 23 ° C. The mixture was stirred for 24 hours. The precipitate was filtered, washed with ethanol (2ml), then dried (vacuum; 55 ° C, 72 hours), yielding 3.7 g (62%) of acid salt 4-arn? No ~ 5-chloro-2,3-d? -hydro-N-Cl- (3-methox? Prop? l) -4-? pep dmil] -7-benzofurancarboxamide (+) - (S) -2-h? droxipropane? co (1: 1); p. of f. 170.4 ° C (compound 3). Compound (2) (5 g, 0.0129 mol) was dissolved in hot ethanol (35 ml) / water (3.5 rnl). Phosphoric acid (0.929 ml) was added and crystallization almost immediately occurred. The mixture was stirred for 24 hours at 23 ° C. The precipitate was filtered, washed with ethanol (2ml), then dried (vacuum; 55 ° C; 72 hours), yielding 5.87 g (97.7%) of acid salt 4-arnmo-5-chloro-2,3-d? H? ro-N-Cl - (3-rnetox? prop? l) -4-p? pe i di i 11-7-benzofurancarboxarnide phosphoric acid (1: 1); p. of f. of 259.6 ° 0 (compound). Compound (2) (5 g, 0.0129 mol) was dissolved in hot ethanol (35 ml) / water (3.5 nl). A solution of 48% brornhydric acid (1.52 rnl) was added, and crystallization almost immediately occurred. The mixture was stirred for 24 hours at 13 ° C. The precipitate was filtered, washed with ethanol (2 ml), then dried (vacuum, 55 ° C, 72 hours), yielding 5.4 g. (93.2%) of 4-arn? No ~ 5-chloro-2, 3-d? H? Dro-N-Cl- (3-rnetoxipropyl) -4-p? Per? D? N hydrobromide? ll-7-benzofurancarboxarnide (1: 1); p. of f. of 280. I ° C (compound 5). The compound (2) (5 g, 0.0129 ol) was dissolved in hot ethanol (25 ml). A solution of succinic acid (1.6 g) in ethanol (10 ml) / water (3.5 ml) was added. After scraping, crystallization occurred. The mixture was stirred for 24 hours at 23 ° C. The precipitate was filtered, washed with ethanol (2ml), then dried (vacuum, 55 ° C, 72 hours), yielding 5.7 g (91%) of 4-ammono-5-chloro-2,3-butanedioate. Hydro-N-Cl- (3-methoxy? propyl) -4-p? per? d? n? ll-7-benzofurancarboxamide (1: 1); p. of f. of 197.2 ° C (compound 6).

EXAMPLE 5 Compound (2) (5 g, 0.0129 mol) was dissolved in ethanol (35 rnl). Water (3.5ml) was added. "Sulfuric acid (0.75 ml) was added dropwise. The mixture was stirred for 24 hours at ± 22 ° C. The precipitate was filtered, washed with ethanol (2 ml), then dried (vacuum, 55-60 ° C, 72 hours), yielding 6.1 g (101%) of 4-amino-5-chloro-2 sulfate, 3-d? H? Dro-Np - (1 -rnetoxiprop? L) -4-p? pepd? n? l] -7-benzofurancarboxarnide (1: 1); p. of f. of 267.5 ° C (compound 7). Compound (2) (5 g, 0.0129 mmol) was dissolved in ethanol (35 ml). Water (3.5 ml) was added. Phosphonate methanesulic acid (0.88 ml) was added dropwise to it. The mixture was stirred, then dried (vacuum, 55-60 ° C, 72 hours), yielding 6 g (100%) of acid salt 4-amino-5-chloro-2,3-d? ~ N- [l- (3-rnet-oxypropyl) -4-? -per? D? N? Ll-7-benzofurancarboxamide (1: 1); p. of f. of 286 ° C (compound 8). Compound (2) (5 g, 0.0129 mol) was dissolved in methyl isobutyl ketone (35 ml), at 60-65 ° C. Acetic acid (0.8rnl) (temperature increase to 75 ° C) was added dropwise. Almost immediately there was precipitation. The mixture was allowed to cool to room temperature. The mixture was stirred for -20 hours. The precipitate was filtered, washed with ethanol (2mL), then dried (vacuum, 55-60 ° C, 72 hours), yielding 5.5 g (99%) of 4-amino-5-chloro-2-salt, 3-d? -hydro-N-Cl- (3-methoxypropyl) -4-??? per? D? N? Ll-7-benzof? -carboxamide acetic acid (1: 1); p. of f.de 156.1 ° C (compound 9).

PHARMACOLOGICAL EXAMPLES EXAMPLE 6 The stimulation of non-adrenergic non-cholinergic nerves produces relaxation followed by a contraction. Relaxation is mediated via a transmitter other than nora enalina, nitric oxide or ATP. The contraction is mediated via a transmitter other than acetylcholine. Guinea pigs Dunkin-Hartley of either sex (350-600 g, not fasting) were sacrificed by cervical dislocation followed by decapitation. The ascending colon was removed and the lumen was cleaned by repeated washing with De Jalón solution. After carefully dissecting the mesentery, the ascending colon was divided into 4 segments of 3 cm in length. Each segment was mounted vertically in an organ bath containing 100 ml of De Jalón solution. The organ bath was maintained at 37 ° C and gasified with a mixture of 95% oxygen and 5% carbon dioxide. To block α, β and muscarinic receptors, phentolamine (10-6 n) t propanolol (3xl0-7 M) and atropine (3xl.O-7 p) were added to the solution. The contractions were measured i.trometrically. The preparation was repeatedly extended until a basal tension of 40 N was obtained and allowed to stabilize for 45 to 60 minutes. Histarnin (3xl0-5 H) was added to the bath solution to obtain maximum shrinkage. Transmural excitation was applied over the entire length of the colon strip by means of two plaoe electrodes, the anode threaded through the colon lumen.; the cathode in the bath solution. The preparation was excited with rectangular square wave pulses (9 V, 1 ms / pulse) for 10 seconds every 5 minutes at different frequencies. The electrical stimulation resulted in a relaxation (- firing response) immediately followed by a contraction (= firing response). Initially, the preparations were stimulated three times at 0.4 Hz to obtain a subrnaxirine relaxation, followed by three stimuli at 1.5 Hz to obtain a sub-maximum contraction. Then, the test compound was added to the bath fluid and again both stimuli (0.4 Hz and 1.5 Hz) were repeated three times. At a concentration of 3 x 10-7 M, the test compound induced an increase in the quench response of 100% of the initial value.

EXAMPLE 7 Guinea pigs DunUn-Hartley of any sex (350 g or more, not fasting) were sacrificed by cervical dislocation followed by decapitation. The descending colon was cut to ± 5 cm from the rectum, cut and ligated to a length of ± 40 cm and released from adherent tissue. When there were at least 10 pellets in the colon, the tissue was transferred to a glass beaker containing 200 ml of Krebs-Henseleit solution, gasified with a mixture of 95% oxygen and 5% carbon dioxide and maintained at 37 ° C. The solution contained pure solvent or the test compound. The expelled pellets were counted and removed from the solution every 5 minutes for a maximum period of 60 minutes. The cumulative number of pellets expelled from the colon at each point was expressed as the percentage of the total number of pellets present in the entire colon at the beginning of the experiment. Time response curves were obtained by plotting the cumulative percentage of pellets expelled from the colon against time. 0 a concentration of 3 x 10-9 n qei compound present, 80% of the initial amount of pellets was expelled within 10 minutes.

EXAMPLE 8 Coaxial stimulation of the ileum in Guinea Pigs D? Nki n-Hartiey guinea pigs of both sexes (body weight ± 500 g) were sacrificed by cervical dislocation followed by decapitation. The ileum was removed and cleaned with heated and oxygenated Krebs-Henseleit solution. Intact non-terminal ileum segments of 4.5 cm in length of the guinea pig were suspended vertically with a preload of 1 g in 100 rnl of Krebs Henseleit solution (37.5 ° C), gasified with a mixture of 95% O2 and 5% CO2 Temporal excitation was applied over the entire length of the ileal segment by means of two platinum electrodes, the threaded node through the lumen of the ileum, the cathode in the bath solution. The preparation was exdtada with individual rectangular stimuli Cl rnseg; 0.1 Hz; subrnaxirna response (current producing an 80% maximum response)] from a programmable stimulator. The contractions were measured imperatively. During the 30 minute stabilization period, the strips were repeatedly extended to a tension of 2 g, to obtain a steady state voltage of 1 g. Before starting the electrical stimulation, a cumulative dose response curve of acetylcholine was given. The electrical stimulation was initiated at supramaxirn current to determine the maximum amplitude of the shaking responses. When these responses were stable, a subrnaxima label to obtain 80% of the maximum responses was given until the shaking responses were constant for at least 15 minutes, after which a single dose of the test compound was added to the test fluid. bath. The amplitude of the shaking response 5 minutes after administration of the test compound is compared to the amplitude before administration of the test compound. The test compound showed an increase in the amplitude of the shaking response of more than 5% at a concentration of 3.10-9 M.

Claims (5)

1. NOVELTY OF THE INVENTION
3. A compound of formula or a pharmaceutically acceptable acid addition salt thereof. 2. A compound as claimed in claim 1, wherein the compound is monohydrochloride of
4. 4-amino-
5. 5-chloro-2,3-dihydro-N-Cl- (3-rnetoxypropyl) -4-piperidinyl] -7-benzofurancarboxarnidamide. 3. A compound as claimed in claim 1, wherein the compound is 4-arnino-5-chloro-2,3-dihydro-N-Cl- (3-methoxypropyl) -4-piperidine-11-butanedioate. 7-benzofurancarboxamide (1: 1). 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in any of claims 1 to 3. 5. A method of preparing a pharmaceutical composition as claimed in claim 4, wherein a therapeutically effective amount of a compound as claimed in any of claims 1 to 3 is intimately mixed with a pharmaceutically acceptable carrier. 6. A compound as claimed in any of claims 1 to 3 for use as a medicine. 7. The use of a compound as claimed in any of claims 1 to 3 for the manufacture of a medicament for the treatment of gastrointestinal motility disorders. 8. The use of a compound as claimed in any of claims 1 to 3 for the manufacture of a medicament for the treatment of constipation. 9. The use of a compound as claimed in any of claims 1 to 3 for the manufacture of a medicament for the treatment of irritable bowel disease. 10. The use of a compound as claimed in any of claims 1 to 3 for the manufacture of a medicament for the treatment of intestinal atony. 11. The use of a compound as claimed in any of claims 1 to 3 for the manufacture of a medicament for the acceleration of the bowel (thick) conduction. 12. A process for the preparation of a compound as claimed in claims 1 or 2, wherein a)? N intermediate of formula (II) is N-alkylated with an alkylating reagent of formula (III), wherein U is an appropriate residual group such as halogen, for example chlorine, or a residual sulfonyloxy group in a solvent inert to the reaction in the presence of an appropriate base; b) an amine of formula (V) is N-acylated with a carboxylic acid of formula (IV) CH3-s (CH2) 3- (O and, if desired, conversion of a compound of formula (I) into a therapeutically active non-toxic addition acid addition salt or, conversely, conversion of an acid addition salt into a free base form with alkali.